CN105769807B - A kind of pharmaceutical composition containing Fenofibric Acid choline - Google Patents
A kind of pharmaceutical composition containing Fenofibric Acid choline Download PDFInfo
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- CN105769807B CN105769807B CN201410792856.7A CN201410792856A CN105769807B CN 105769807 B CN105769807 B CN 105769807B CN 201410792856 A CN201410792856 A CN 201410792856A CN 105769807 B CN105769807 B CN 105769807B
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- CN
- China
- Prior art keywords
- fenofibric acid
- acid choline
- pharmaceutical composition
- lauryl sulfate
- choline
- Prior art date
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- 229960000701 fenofibric acid Drugs 0.000 title claims abstract description 74
- MQOBSOSZFYZQOK-UHFFFAOYSA-N fenofibric acid Chemical compound C1=CC(OC(C)(C)C(O)=O)=CC=C1C(=O)C1=CC=C(Cl)C=C1 MQOBSOSZFYZQOK-UHFFFAOYSA-N 0.000 title claims abstract description 74
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 title claims abstract description 65
- 229960001231 choline Drugs 0.000 title claims abstract description 65
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 17
- 229920000896 Ethulose Polymers 0.000 claims abstract description 30
- 239000001859 Ethyl hydroxyethyl cellulose Substances 0.000 claims abstract description 30
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 claims abstract description 30
- 229940043264 dodecyl sulfate Drugs 0.000 claims abstract description 30
- 235000019326 ethyl hydroxyethyl cellulose Nutrition 0.000 claims abstract description 30
- 239000000945 filler Substances 0.000 claims abstract description 9
- 239000000314 lubricant Substances 0.000 claims abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 38
- 238000002360 preparation method Methods 0.000 claims description 25
- 239000002775 capsule Substances 0.000 claims description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 17
- 238000007873 sieving Methods 0.000 claims description 17
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 16
- 238000001035 drying Methods 0.000 claims description 15
- 238000005550 wet granulation Methods 0.000 claims description 15
- 239000011248 coating agent Substances 0.000 claims description 14
- 238000000576 coating method Methods 0.000 claims description 14
- 239000000843 powder Substances 0.000 claims description 14
- 239000000741 silica gel Substances 0.000 claims description 13
- 229910002027 silica gel Inorganic materials 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 10
- 229920002472 Starch Polymers 0.000 claims description 9
- 239000008107 starch Substances 0.000 claims description 9
- 235000019698 starch Nutrition 0.000 claims description 9
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 8
- 229930195725 Mannitol Natural products 0.000 claims description 8
- 235000019359 magnesium stearate Nutrition 0.000 claims description 8
- 239000000594 mannitol Substances 0.000 claims description 8
- 235000010355 mannitol Nutrition 0.000 claims description 8
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 claims description 7
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 7
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 7
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 7
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 6
- -1 ethyl hydroxyl Chemical group 0.000 claims description 6
- 229940049654 glyceryl behenate Drugs 0.000 claims description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 4
- 229920000881 Modified starch Polymers 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 claims description 4
- 235000000346 sugar Nutrition 0.000 claims description 4
- 229920002678 cellulose Polymers 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 235000010980 cellulose Nutrition 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- 150000001990 dicarboxylic acid derivatives Chemical class 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000005516 engineering process Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 27
- 238000012360 testing method Methods 0.000 description 16
- 238000000034 method Methods 0.000 description 15
- 235000019441 ethanol Nutrition 0.000 description 13
- 239000012535 impurity Substances 0.000 description 13
- 239000002253 acid Substances 0.000 description 11
- BFRLRGJQKQUFHK-UHFFFAOYSA-N 2,2-bis(hydroxymethyl)propane-1,3-diol;phthalic acid Chemical compound OCC(CO)(CO)CO.OC(=O)C1=CC=CC=C1C(O)=O BFRLRGJQKQUFHK-UHFFFAOYSA-N 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 239000002702 enteric coating Substances 0.000 description 5
- 238000009505 enteric coating Methods 0.000 description 5
- 238000011068 loading method Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000013558 reference substance Substances 0.000 description 4
- 239000000661 sodium alginate Substances 0.000 description 4
- 235000010413 sodium alginate Nutrition 0.000 description 4
- 229940005550 sodium alginate Drugs 0.000 description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000012488 sample solution Substances 0.000 description 3
- 235000015170 shellfish Nutrition 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000003524 antilipemic agent Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 229960002297 fenofibrate Drugs 0.000 description 2
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 description 2
- 229940125753 fibrate Drugs 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000003595 mist Substances 0.000 description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 0.000 description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
- RUETVLNXAGWCDS-UHFFFAOYSA-N (4-chlorophenyl)-(4-hydroxyphenyl)methanone Chemical compound C1=CC(O)=CC=C1C(=O)C1=CC=C(Cl)C=C1 RUETVLNXAGWCDS-UHFFFAOYSA-N 0.000 description 1
- XDHYHJRKXJFCBM-UHFFFAOYSA-N (4-chlorophenyl)-[4-(2-hydroxypropan-2-yl)phenyl]methanone Chemical compound C1=CC(C(C)(O)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 XDHYHJRKXJFCBM-UHFFFAOYSA-N 0.000 description 1
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- YAVVGPBYBUYPSR-UHFFFAOYSA-N benzene;oxygen Chemical compound [O].C1=CC=CC=C1 YAVVGPBYBUYPSR-UHFFFAOYSA-N 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 229910001914 chlorine tetroxide Inorganic materials 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000012055 enteric layer Substances 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 230000009246 food effect Effects 0.000 description 1
- 235000021471 food effect Nutrition 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 208000006575 hypertriglyceridemia Diseases 0.000 description 1
- 239000000138 intercalating agent Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000006636 nicotinic acid Chemical class 0.000 description 1
- 238000005453 pelletization Methods 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
Abstract
The invention belongs to pharmaceutical technology fields, and in particular to a kind of pharmaceutical composition containing Fenofibric Acid choline, the pharmaceutical composition contain Fenofibric Acid choline, filler, lubricant, ethylhydroxyethylcellulose and sldium lauryl sulfate.Product stability of the invention of the invention is good, and release completely, has more outstanding product quality；Operation is simple for production of the invention, is suitable for industrial production.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of pharmaceutical composition and its piece containing Fenofibric Acid choline
The preparation method of agent.
Background technique
Cardiovascular disease is to endanger that human health (especially person in middle and old age) is most common, one of disease of most serious, and blood lipid is different
It is often the important risk factor of atherosclerosis, coronary heart disease and other cardiovascular and cerebrovascular diseases, fat regulation medicine can reduce these diseases
The incidence and the death rate of disease generate positive effect and far-reaching influence to the prevention and treatment of cardiovascular disease.
The statistical data of IMS Health company, the U.S. shows that global lipid lowering agent market in 2008 has reached 338.49
Hundred million dollars, year-on-year upper one year increases 1.75%, accounts for the 4.38% of Global Medicine market, is to be only second to anti-tumor drug and occupy the
Two important specieses.
On global drug markets in 2009, ranks among 15 in the last 500 lipid lowering agents and have reached 28,500,000,000 dollars, on year-on-year basis
Upper one year increases 1.11%, accounts for the 6.6% of the last 500 medicine sales total value, is to be only second to tumour in preceding 10 major class principal item
With the kind for occuping third position after hypertension medication.
Clinical application at present and the lipid-loweringing Western medicine for being in development phase can be divided into him by its lipid-loweringing mechanism and chemical structure again
Spit of fland class, niacin class, fibrates, cholic acid intercalating agent class, polyenoid class and novel lipid-lowering medicine and various compound preparations.
Fenofibric Acid (English name Fenofibric Acid), its chemical name is: 2- [4- (4- chlorobenzene formacyl) benzene oxygen
Base] -2 Methylpropionic acid.Molecular formula: C17H15ClO4, molecular weight: 318.75, structural formula is as follows:
Fenofibric Acid is second generation fibrate drug, for treating hypercholesterolemia and hypertriglyceridemia,
It is fenofibrate in the intracorporal metabolite of people and effective component, there is high solubility in small intestine area, therefore, compared to non-
Nobert has better bioavilability, and bioavilability is not by food effect.
Chinese patent CN102172347A discloses a kind of preparation process of Fenofibric Acid enteric-soluble controlled-release capsule, pass through by
Pelletizing press sheet forms microplate, and each microplate diameter about 3mm is then enteric coated on microplate again, then the microplate after coating is packed into
Enteric-soluble controlled-release capsule is made in capsule.But it also needs that filling is further processed after the completion of prepared by microplate using microplate technique
Capsule is made to facilitate patient to take, and it also requires using certain moduli tool and sheeting equipment, production efficiency is relatively low and consumes
Duration.
Chinese patent CN101780049A discloses a kind of preparation method of Fenofibric Acid enteric coated preparations, wraps on pellet
Fenofibric Acid active constituent is wrapped up in, then wraps barrier gown and enteric layer again, enteric suspension is made.However, using pellet technique
It needs fluidized bed bottom to spray packaging technique, is repeatedly coated on pellet, long processing time, made suspension is unfavorable for patient's clothes
With dosage is not easy to control.
The above data does not mention Fenofibric Acid choline tablet and preparation method thereof.Prepare a kind of Fenofibric Acid choline system
Agent, and have the characteristics that related substance is few, dissolution is complete, quality is stable, it is desirable to guarantee stabilization, the safety of clinical drug effect
Those skilled in the art put forth effort the technical issues of solving.
Summary of the invention
For these reasons, applicant has found a kind of pharmaceutical composition of new Fenofibric Acid choline, the medicine after study
Contain sldium lauryl sulfate and ethylhydroxyethylcellulose in compositions, on the basis of guaranteeing release, is further ensured that non-
The impurity of promise shellfish acid choline composes stability.
The object of the present invention is to provide a kind of new pharmaceutical composition containing Fenofibric Acid choline, the composition is prepared into
Preparation, have the advantages that release is good, impurity compose it is stable.
It is another object of the present invention to provide a kind of preparation method of pharmaceutical composition containing Fenofibric Acid choline,
This method is suitble to industrial production.
Specifically, the present invention provides:
A kind of pharmaceutical composition containing Fenofibric Acid choline, contains: Fenofibric Acid choline, filler, lubricant, ethyl
Hydroxyethyl cellulose and sldium lauryl sulfate.
The pharmaceutical composition containing Fenofibric Acid choline, the weight ratio of each component are as follows:
1 ~ 4 parts by weight of Fenofibric Acid choline
0.3 ~ 0.8 parts by weight of ethylhydroxyethylcellulose
1 ~ 5 parts by weight of sldium lauryl sulfate
30 ~ 60 parts by weight of filler
1 ~ 5 parts by weight of lubricant.
The weight ratio of the ethylhydroxyethylcellulose and sldium lauryl sulfate is 1:(4 ~ 6.3).
The filler be selected from one of starch, lactose, Icing Sugar, mannitol, microcrystalline cellulose, pregelatinized starch or
It is several.
The lubricant is selected from one or more of superfine silica gel powder, talcum powder, magnesium stearate, glyceryl behenate.
The pharmaceutical composition containing Fenofibric Acid choline is prepared into capsulae enterosolubilis.
The preparation method of the pharmaceutical composition containing Fenofibric Acid choline, comprising the following steps: by Fenofibric Acid
Choline, ethylhydroxyethylcellulose, sldium lauryl sulfate, filler, lubricant are sieved respectively, mix, wet granulation, sieving,
With in boiling-bed drying, loading capsule is up to Fenofibric Acid choline after the ethanol solution coating of pentaerythritol phthalate
Capsulae enterosolubilis.
Compared with the prior art, the present invention has the following advantages and good effect:
1, product stability of the invention is good, and release is complete.
2, operation is simple for production of the invention, is suitable for industrial production.
Specific embodiment
The following describes the present invention further through the description of specific embodiments, but it is to limit of the invention that this, which is not,
System, those skilled in the art's basic thought according to the present invention can make various modifications or improvements, but without departing from this
The basic thought of invention, is all within the scope of the present invention.
Test method
Release is protected from light operation.This product is taken, according to drug release determination method (two annex X D of Chinese Pharmacopoeia version in 2010
Second method), using the second subtraction unit of dissolution method, with pH 3.5 ± 0.05 sodium phosphate buffer (1M sodium dihydrogen phosphate: 1M
Phosphoric acid: water=50:8:942, is dissolution medium with 1M sodium dihydrogen phosphate or 1M phosphoric acid tune pH) 500ml, and revolving speed is per minute 50
Turn, operate according to methods, through 2 hours, take solution appropriate, filters, take subsequent filtrate as acid-resistant strength test solution.In above-mentioned acid solution
In, 37 DEG C of 0.05mol/L disodium phosphate soln 400ml is added immediately, mixes, continues to operate, through 1 hour, 2 hours, it is 3 small
When and at 4 hours, take solution to filter respectively, take subsequent filtrate as release test solution (2), (3), (4), (5), and in time
Supplement the dissolution medium of mutually synthermal same volume.Separately take Fenofibric Acid choline reference substance appropriate, it is accurately weighed, add pH6.8 to be situated between
Matter dissolves and quantifies the solution for diluting and being made in every 1ml containing about 0.05mg, as release reference substance solution.Take above-mentioned test sample
Solution and reference substance solution are measured according to the method under content determination item, calculate every release.
Related substance is protected from light operation.Take the fine powder under this product content determination item appropriate, accurately weighed, (water (uses phosphorus to solubilizer
Acid for adjusting pH value dissolves to 2.5)-acetonitrile (30:70)) and quantifies the solution for diluting and being made in every 1ml containing about 0.5mg, as confession
Test sample solution；Precision measures in right amount, is made with solvent dilution containing about the solution of 0.5 μ g in every 1ml, as contrast solution；Take confession
Test sample solution illumination 10 minutes, as system suitability solution.According to high performance liquid chromatography (Chinese Pharmacopoeia version two in 2010
V D of portion's annex) measurement.It is with octadecylsilane chemically bonded silica (recommending Wondasil C18,5 μm, 4.6 × 250mm)
Filler, using acetonitrile as Mobile phase B, carries out linear gradient according to following table with water (with phosphorus acid for adjusting pH value to 2.5) for mobile phase A
Elution；Detection wavelength is 286nm.10 μ l of system suitability solution is taken to inject liquid chromatograph, the reservation at Fenofibric Acid peak
Time is about 16~18 minutes, and Fenofibric Acid peak and II peak of impurity (relative retention time is about 0.9), III peak of impurity are (opposite to protect
Staying the time is about that 2.36) should meet the requirements with the separating degree of IV peak of impurity (relative retention time is about 2.42).Take contrast solution
10 μ l inject liquid chromatograph, adjust detection sensitivity, making the peak height of principal component chromatographic peak is about the 10% of full scale；It is accurate again
Test solution and each 10 μ l of contrast solution are measured, liquid chromatograph is injected separately into, records chromatogram.
Impurity I (RRT=0.65)
Chinese: the chloro- 4` dihydroxy benaophenonel of 4-
English name: 4-Chloro-4'-hydroxybenzophenone
Impurity II (RRT=0.9)
Chinese: (4- chlorphenyl) [4-(2- hydroxypropyl -2- base) phenyl] ketone
English name: (4-chlorophenyl) (4- (2-hydroxypropan-2-yl) phenyl) methanone
Impurity IV (RRT=2.42)
Chinese: (4- chlorphenyl) [4-(1- methoxyl group) phenyl]-ketone
English name: (4-chlorobenzoyl) [4-(1-methylthoxy) phenyl]-methanone
Assay is measured according to high effective liquid chromatography for measuring (two V D of annex of Chinese Pharmacopoeia version in 2010).
Chromatographic condition and system suitability are filler with octadecylsilane chemically bonded silica；With water (with phosphoric acid tune
It is mobile phase, Detection wavelength 286nm that pH value, which is saved, to 2.5)-acetonitrile (50:50).This product fine powder is taken (to be approximately equivalent to non-promise in right amount
Shellfish acid 10mg), it sets in 100ml measuring bottle, solubilizer dissolves and be diluted to scale, shakes up, illumination 5~10 minutes, and precision measures 10 μ
L injects liquid chromatograph, and number of theoretical plate is calculated by Fenofibric Acid peak is not less than 3000, point at Fenofibric Acid peak and other impurities peak
It should meet the requirements from degree.
Measuring method takes this product 20, and accurately weighed, the average loading amount of calculating takes content finely ground, precision weighs in right amount (about
It is equivalent to Fenofibric Acid 10mg), it sets in 100ml measuring bottle, solubilizer (water (with phosphorus acid for adjusting pH value to 2.5)-acetonitrile (30:70))
Make to dissolve and be diluted to scale, shake up, filter, take 10 μ 1 of subsequent filtrate, inject liquid chromatograph, records chromatogram；Another negated promise
Shellfish acid reference substance about 10mg, it is accurately weighed, it sets in 100ml measuring bottle, solubilizer dissolves and be diluted to scale, shakes up, and is measured in the same method.
By external standard method with calculated by peak area to get.
Test example 1: prescription screening test
Take Fenofibric Acid choline 3.5g(content 99.9% respectively, it is total it is miscellaneous 0.09%), starch 35g, glyceryl behenate 1.8g,
The capsulae enterosolubilis containing Fenofibric Acid choline is made by following prescriptions, detects related substance and release, the results are shown in Table 2:
1 prescription screening of table
Enteric coating liquid 1#: 1% low-viscosity sodium alginate aqueous solution.
Enteric coating liquid 2#: 96% ethanol solution of pentaerythritol phthalate；
Enteric coating liquid 3#: metering system acid dispersant.
1 preparation method of prescription: Fenofibric Acid choline, starch, superfine silica gel powder, povidone are sieved respectively, mixed, wet process system
Grain, sieving, in boiling-bed drying, loading capsule is up to Fenofibric Acid choline after the coating of 1% low-viscosity sodium alginate aqueous solution
Capsulae enterosolubilis.
2 preparation method of prescription: Fenofibric Acid choline, starch, superfine silica gel powder, ethylhydroxyethylcellulose are sieved respectively,
It mixes, wet granulation, sieving, in boiling-bed drying, loading capsule after the coating of 1% low-viscosity sodium alginate aqueous solution to obtain the final product
Fenofibric Acid choline capsulae enterosolubilis.
3 preparation method of prescription: Fenofibric Acid choline, starch, superfine silica gel powder, sldium lauryl sulfate being sieved respectively, mixed,
Wet granulation, sieving, in boiling-bed drying, loading capsule is up to fenofibrate after the coating of 1% low-viscosity sodium alginate aqueous solution
Sour choline capsulae enterosolubilis.
4 ~ 8 preparation method of prescription: by Fenofibric Acid choline, starch, superfine silica gel powder, ethylhydroxyethylcellulose, laruyl alcohol
Sodium sulphate is sieved respectively, mixes, wet granulation, sieving, and after being coated with enteric coating liquid in boiling-bed drying, being packed into capsule is
Obtain Fenofibric Acid choline capsulae enterosolubilis.
Table 2 is in relation to substances test result
Test result shows: Fenofibric Acid choline and ethylhydroxyethylcellulose are dissolved in system made from sldium lauryl sulfate
The related substance of agent is better than other methods；In addition, selecting 96% ethanol solution of pentaerythritol phthalate as enteric coating
The release of capsule made from liquid is better than other coating solutions.
Test example 2: influence factor test
3,5,6,8 product of Example carries out influence factor test, the results are shown in Table 3.
3 influence factor test data of table
Conclusion: road as seen from the above table is had good by product prepared by the method for the present invention under high temperature and illumination, high humidity
Stability, single impurity level is below 0.1%, and total impurities amount is lower than 0.25%.
Test example 3: accelerated test
5,6,8 product of Example carries out accelerated test, the results are shown in Table 4.
4 accelerated test data of table
Packaging: commercially available back, investigation condition: 40 DEG C of temperature, humidity 75%
Conclusion: road as seen from the above table has good stabilization by product prepared by the method for the present invention under accelerated test
Property, single impurity level is below 0.1%, and total impurities amount is lower than 0.35%.
Preparation example
Embodiment 1
Prescription
Fenofibric Acid choline 1.0g
Ethylhydroxyethylcellulose 0.7g
Sldium lauryl sulfate 3.6g
Starch 35g
Superfine silica gel powder 1.8g.
Preparation method: by Fenofibric Acid choline, ethylhydroxyethylcellulose, sldium lauryl sulfate, starch, superfine silica gel powder point
It Guo Shai, not mix, wet granulation, sieving, in boiling-bed drying after being coated with the ethanol solution of pentaerythritol phthalate
In, capsule is packed into up to Fenofibric Acid choline capsulae enterosolubilis.
Embodiment 2
Prescription
Fenofibric Acid choline 1.5g
Ethylhydroxyethylcellulose 0.4g
Sldium lauryl sulfate 2.0g
Lactose 38g
Talcum powder 2.8g.
Preparation method: Fenofibric Acid choline, ethylhydroxyethylcellulose, sldium lauryl sulfate, lactose, talcum powder are distinguished
Sieving mixes, wet granulation, sieving, after being coated with the ethanol solution of pentaerythritol phthalate in boiling-bed drying,
Capsule is packed into up to Fenofibric Acid choline capsulae enterosolubilis.
Embodiment 3
Prescription
Fenofibric Acid choline 2.0g
Ethylhydroxyethylcellulose 0.6g
Sldium lauryl sulfate 2.8g
Icing Sugar 45g
Glyceryl behenate 2.5g.
Preparation method: by Fenofibric Acid choline, ethylhydroxyethylcellulose, sldium lauryl sulfate, Icing Sugar, glycerol behenic acid
Ester is sieved respectively, mixes, wet granulation, sieving, is done with after the ethanol solution coating of pentaerythritol phthalate in boiling
In dry bed, capsule is packed into up to Fenofibric Acid choline capsulae enterosolubilis.
Embodiment 4
Prescription
Fenofibric Acid choline 2.5g
Ethylhydroxyethylcellulose 0.7g
Sldium lauryl sulfate 3.6g
Mannitol 54g
Magnesium stearate 2.5g.
Preparation method: by Fenofibric Acid choline, ethylhydroxyethylcellulose, sldium lauryl sulfate, mannitol, magnesium stearate
It is sieved, mixes, wet granulation respectively, sieving, in fluidized drying after being coated with the ethanol solution of pentaerythritol phthalate
In bed, capsule is packed into up to Fenofibric Acid choline capsulae enterosolubilis.
Embodiment 5
Prescription
Fenofibric Acid choline 3.0g
Ethylhydroxyethylcellulose 0.8g
Sldium lauryl sulfate 3.2g
Microcrystalline cellulose 37g
Superfine silica gel powder 1.2g
Magnesium stearate 0.5g.
Preparation method: by Fenofibric Acid choline, ethylhydroxyethylcellulose, sldium lauryl sulfate, microcrystalline cellulose, micro mist
Silica gel and magnesium stearate are sieved respectively, mix, and cross 20 meshes, mix 20 minutes, wet granulation, sieving, with pentaerythrite neighbour's benzene
After the ethanol solution coating of dicarboxylic acid esters in boiling-bed drying, capsule is packed into up to Fenofibric Acid choline capsulae enterosolubilis.
Embodiment 6
Prescription
Fenofibric Acid choline 3.5g
Ethylhydroxyethylcellulose 0.5g
Sldium lauryl sulfate 1.8g
Microcrystalline cellulose 85g
Talcum powder 0.8g
Magnesium stearate 0.5g.
Preparation method: by Fenofibric Acid choline, ethylhydroxyethylcellulose, sldium lauryl sulfate, microcrystalline cellulose, talcum
Powder, magnesium stearate are sieved respectively, mix, and cross 20 meshes, mix 20 minutes, wet granulation, sieving, with pentaerythrite O-phthalic
After the ethanol solution coating of acid esters in boiling-bed drying, capsule is packed into up to Fenofibric Acid choline capsulae enterosolubilis.
Embodiment 7
Prescription
Fenofibric Acid choline 4.0g
Ethylhydroxyethylcellulose 0.3g
Sldium lauryl sulfate 1.3g
Pregelatinized starch 53g
Glyceryl behenate 4g.
Preparation method: by Fenofibric Acid choline, ethylhydroxyethylcellulose, sldium lauryl sulfate, pregelatinized starch, glycerol
Behenate is sieved respectively, mixes, and crosses 20 meshes, mixes 20 minutes, wet granulation, sieving, with pentaerythrite phthalic acid
After the ethanol solution coating of ester in boiling-bed drying, capsule is packed into up to Fenofibric Acid choline capsulae enterosolubilis.
Embodiment 8
Prescription
Fenofibric Acid choline 1.0g
Ethylhydroxyethylcellulose 0.75g
Sldium lauryl sulfate 3.5g
Microcrystalline cellulose 48g
Superfine silica gel powder 1.5g.
Preparation method: by Fenofibric Acid choline, ethylhydroxyethylcellulose, sldium lauryl sulfate, crystalline cellulose, micro mist silicon
Glue is sieved respectively, mixes, and crosses 20 meshes, mixes 20 minutes, wet granulation, sieving, with the second of pentaerythritol phthalate
After alcoholic solution coating in boiling-bed drying, capsule is packed into up to Fenofibric Acid choline capsulae enterosolubilis.
Embodiment 9
Prescription
Fenofibric Acid choline 2.0g
Ethylhydroxyethylcellulose 0.3g
Sldium lauryl sulfate 1.2g
Mannitol 60g
Glyceryl behenate 3g.
Preparation method: by Fenofibric Acid choline, ethylhydroxyethylcellulose, sldium lauryl sulfate, mannitol, glycerol behenyl
Acid esters is sieved respectively, mixes, and crosses 20 meshes, mixes 20 minutes, wet granulation, sieving, with pentaerythritol phthalate
After ethanol solution coating in boiling-bed drying, capsule is packed into up to Fenofibric Acid choline capsulae enterosolubilis.
Embodiment 10
Prescription
Fenofibric Acid choline 4.0g
Ethylhydroxyethylcellulose 0.8g
Sldium lauryl sulfate 3.1g
Mannitol 10g
Superfine silica gel powder 5g.
Preparation method: by Fenofibric Acid choline, ethylhydroxyethylcellulose, sldium lauryl sulfate, mannitol, superfine silica gel powder
It is sieved, mixes respectively, cross 20 meshes, mix 20 minutes, wet granulation, sieving, with the ethyl alcohol of pentaerythritol phthalate
After solution coating in boiling-bed drying, capsule is packed into up to Fenofibric Acid choline capsulae enterosolubilis.
Claims (3)
1. a kind of pharmaceutical composition containing Fenofibric Acid choline, it is characterised in that the weight ratio of each component in pharmaceutical composition
Are as follows:
The weight ratio of the ethylhydroxyethylcellulose and sldium lauryl sulfate is 1:4~6.3；
Pharmaceutical composition is prepared into capsulae enterosolubilis；Wherein capsulae enterosolubilis the preparation method comprises the following steps: by Fenofibric Acid choline, ethyl hydroxyl second
Base cellulose, sldium lauryl sulfate, filler, lubricant are sieved respectively, mix, wet granulation, sieving, with pentaerythrite neighbour's benzene
After the ethanol solution coating of dicarboxylic acid esters in boiling-bed drying, it is packed into capsule to obtain the final product.
2. the pharmaceutical composition according to claim 1 containing Fenofibric Acid choline, it is characterised in that the filler
Selected from one or more of starch, lactose, Icing Sugar, mannitol, microcrystalline cellulose, pregelatinized starch.
3. the pharmaceutical composition according to claim 1 containing Fenofibric Acid choline, it is characterised in that the lubricant
Selected from one or more of superfine silica gel powder, talcum powder, magnesium stearate, glyceryl behenate.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1726024A (en) * | 2002-12-17 | 2006-01-25 | 阿伯特有限及两合公司 | Formulation comprising fenofibric acid, a physiologically acceptable salt or derivative thereof |
| CN1867321A (en) * | 2003-10-10 | 2006-11-22 | 生命周期药物公司 | A solid dosage form comprising a fibrate |
| CN103083275A (en) * | 2013-01-31 | 2013-05-08 | 扬子江药业集团有限公司 | Enteric coated tablet of fenofibric acid and physiologically acceptable salts and preparation method of enteric coated tablet |
| CN104173313A (en) * | 2014-08-25 | 2014-12-03 | 杭州朱养心药业有限公司 | Rivaroxaban troche pharmaceutical composition |
-
2014
- 2014-12-20 CN CN201410792856.7A patent/CN105769807B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1726024A (en) * | 2002-12-17 | 2006-01-25 | 阿伯特有限及两合公司 | Formulation comprising fenofibric acid, a physiologically acceptable salt or derivative thereof |
| CN1867321A (en) * | 2003-10-10 | 2006-11-22 | 生命周期药物公司 | A solid dosage form comprising a fibrate |
| CN103083275A (en) * | 2013-01-31 | 2013-05-08 | 扬子江药业集团有限公司 | Enteric coated tablet of fenofibric acid and physiologically acceptable salts and preparation method of enteric coated tablet |
| CN104173313A (en) * | 2014-08-25 | 2014-12-03 | 杭州朱养心药业有限公司 | Rivaroxaban troche pharmaceutical composition |
Non-Patent Citations (1)
| Title |
|---|
| 非诺贝酸胆碱盐缓释片的制备及体内外评价;陆步实等;《中国医药工业杂志》;20131231;第44卷(第9期);第900-903页 |
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Denomination of invention: A drug combination containing non norepinephrine choline Effective date of registration: 20231226 Granted publication date: 20190315 Pledgee: China Construction Bank Co.,Ltd. Changchun Science and Technology Sub branch Pledgor: CHANGCHUN HAIYUE PHARMACEUTICAL Co.,Ltd. Registration number: Y2023220000149 |
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